MicroRNA-mediated regulation of the angiogenic switch

Abstract

Purpose of review: It has been known for decades that in order to grow, tumors need to activate quiescent endothelial cells to form a functional vascular network, a process termed 'angiogenesis'. However, the molecular determinants that reverse this endothelial quiescence to facilitate pathological angiogenesis are not yet completely understood. This review examines a critical regulatory switch at the level of Ras that activates this angiogenic switch process and the role that microRNAs play in this process.

Recent findings: In the last few years, microRNAs, a new class of small RNA molecules, have emerged as key regulators of several cellular processes, including angiogenesis. MicroRNAs such as miR-126, miR-296, and miR-92a have been shown to play important roles in angiogenesis. We recently described how miR-132, an angiogenic growth factor inducible microRNA in the endothelium, facilitates pathological angiogenesis by downregulating p120RasGAP, a molecular brake for Ras. Importantly, targeting miR-132 with a complementary, synthetic antimicroRNA restored the brake and decreased angiogenesis and tumor burden in multiple tumor models. Taken together, emerging evidence suggests a central role for microRNAs downstream of multiple growth factors in regulating endothelial proliferation, migration, and vascular patterning.

Summary: Further research into miR-132-p120RasGAP biology and more broadly, microRNA regulation of Ras pathways in the endothelium will not only advance our understanding of angiogenesis but also provide opportunities for therapeutic intervention.

Figure 1. miR-132 regulation of p120RasGAP as an angiogenic switch for tumorigenesis

Tumors secrete growth factors that trigger phosphorylation of CREB and subsequent transcription of miR-132. miR-132 downregulates p120RasGAP thereby removing the endogenous brake on Ras activity and activates quiescent endothelium. Inhibition of miR-132 with an anti-miR restores p120RasGAP expression and dampens endothelial activation to inhibit angiogenesis and tumor growth.